OVERVIEW: What every practitioner needs to know

Are you sure your patient has Hodgkin lymphoma? What are the typical findings for this disease?

Hodgkin Lymphoma (HL) is a malignant neoplasm arising from lymphoid cells. HL is a common cancer in adolescents and young adults. Typically HL occurs in lymph nodes in the neck and anterior mediastium but can occur throughout the body. Patients will present with lymphadenopathy or B-symptoms such as fever, night sweats, and weight loss. Patients are treated with multiagent systemic chemotherapy with or without radiation therapy. Most patients will survive this disease so close attention needs to be paid to long-term effects of chemotherapy including organ damage and secondary malignancy.

How do you risk-stratify pediatric Hodgkin lymphoma?

Risk stratification for treatment purposes is specific for each treatment cooperative group. In the American and European cooperative groups, three risk categories are used. There are differences between the groups. The outline below includes the definitions used by the major American cooperative group, Children's Oncology Group, in their recently completed clinical trials.

Nodular sclerosis most common in adolescents followed by mixed cellularity

Outcomes for mixed cellularity in children and adolescents are better than for Nodular Sclerosis

Newer regimens will take this into account

Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL)

What is Nodular Lymphocyte-Predominant Hodgkin Lymphoma (NLPHL or LP Hodgkin)?

Different pathology and immunophenotype than classical Hodgkin Lymphoma

Lymphcytic and Histiocytic cells (L&H cells)

Large mononuclear cells

Different epidemiology than classical Hodgkin Lymphoma

More common in boys

More common in children less than 10 years

Typically presents with asymptomatic peripheral lymphadenopathy

Localized and nonbulky

Does not usually involve the mediastinum

Excellent prognosis with minimal treatment

Complete resection of single involved lymph node may be adequate therapy

Chemotherapy for more advanced disease

Radiation only for persistent disease

Adult-onset NLPHL is a separate entity

Response to treatment different

Adult-onset NLPHL minimal sensitive to chemotherapy and very responsive to radiation therapy

If you are able to confirm that the patient has Hodgkin lymphoma, what treatment should be initiated?

Immediate management

All children suspected of having Hodgkin Lymphoma should be referred to a pediatric oncology specialist.

If available, all children should be offered participation in a therapeutic clinical trial.

Consider inpatient admission for rapid evaluation and management

Depends on severity of symptoms, particularly respiratory distress or orthopnea

Urgency required if large mediastinal mass due to concern for superior vena cava syndrome

Superior vena cava syndrome occurs when return of blood flow to the heart from the head and neck is compromised by compression of the great vessels by tumor

Common symptoms include dyspnea, cough, arm and face swelling, and sensation of head fullness

Cerebral edema can develop leading to headache, confusion, and coma

Avoid administration of corticosteroids until after diagnosis is confirmed

Disease-directed treatment depends on risk stratification

Typically includes multiagent systemic chemotherapy with or without radiation therapy

Ongoing therapy based on response

Resolution of FDG_PET avidity

Improvement in lesion size by CT

Normalization of ESR and other laboratory markers of disease

Length of therapy 3-6 months

What are the treatment options for newly diagnosed Hodgkin Lymphoma?

At most centers in the United States, treatment for Hodgkin Lymphoma includes three to five cycles of multiagent chemotherapy depending on initial risk categorization and response to treatment.

Chemotherapy agents typically include (ABVE-PC):

Doxorubicin (A)

Bleomycin (B)

Vincristine (V)

Etoposide (E)

Prednisone (P)

Cylcophosphamide (C)

Brentuximab Vedotin is a promising new targeted agent

Anti-CD30 monoclonal antibody linked to a cytotoxic agent

Currently in clinical trials for frontline and relapsed HL

Patients with slow initial response to chemotherapy may have treatment intensified with additional cycles of chemotherapy or alterative regimens which have shown activity in relapsed or refractory patients depending on the protocol.

Radiation therapy:

Low dose involved field radiation

Radiation directly only at lymph node areas shown to be involved with disease at diagnosis

Dose between commonly between 15 and 25 cGy -- usually 21 cGy --

Used in most pediatric clinical trials

Dose and volume of radiation therapy highly protocol specific due to ongoing research objectives

Recent approaches will use involved nodal radiation and may be restricted to areas with bulky or persistent disease.

Recent clinical studies from the Children's Oncology Group are evaluating for which patients radiation therapy can be safely omitted.

What are the treatment options for relapsed or refractory Hodgkin Lymphoma?

If available, all children should be offered participation in a therapeutic clinical trial.

Additional chemotherapy:

Any standard regimens not used for the patient with initial disease may be considered.

Gemcitabine and Vinorelbine

Brentuximab Vedotin as single agent or in combination with other agents

Regimens including etoposide (e.g., ifosphamide, cisplatin, and etoposide (ICE)) are not preferred prior to stem cell harvest as the risk of secondary malignancy may be increased.

Radiation therapy:

Particularly useful if patient has not been radiated previously or disease is outside original radiation field.

Hematopoietic stem cell transplant:

Should be considered for all patients who achieve good response to retrieval therapy.

Event free survival of about 20% if patient has chemotherapy resistant disease.

Typically includes high dose chemotherapy followed by autologous stem cell rescue.

Interest in immune-modulation or reduced intensity allogeneic transplantation to improve outcome for those with resistant disease.

Ongoing clinical trials and laboratory investigations are looking for new agents and therapeutic approaches.

What are the adverse effects associated with each treatment option?

Chemotherapy -

Immediate effects of chemotherapy:

Common side effects of chemotherapy include nausea/vomiting, alopecia, and hematologic suppression. Hematologic suppression can result in fatigue (anemia), bleeding (thrombocytopenia), and risk for infection (neutropenia).

How can Hodgkin lymphoma be prevented?

What is the evidence?

(This is a website maintained by the National Cancer Institute to provide up-to-date information on pediatric Hodgkin Lymphoma and its treatment written for both patients and health professionals. Information on this site is reviewed and updated frequently by national experts in the field.)

(This paper presents the most recent Children's Oncology Group strategy for evaluation, treatment, and research in pediatric Hodgkin lymphoma including reduction in exposure to radiation therapy, a new prognostic factor score, and novel retrieval regimens.)

(This paper reports results from a Children's Cancer Group study which treated patients with combination chemotherapy and randomized them to radiation or no radiation. Patients treated without radiation had a slightly increased risk of relapse, but no survival benefit to radiation has been shown. This study is one of the basis for continuing investigation in the Children's Oncology Group on the appropriate role of radiation therapy for children with Hodgkin Lymphoma.)

(This paper reports results from a Pediatric Oncology Group study which treated patients with novel combination chemotherapy designed to minimize risk for late effects of therapy and low dose involved field radiation therapy. Patients treated with this regimen enjoyed excellent outcomes while receiving cumulative doses of key chemotherapy agents below thresholds usually associated with significant long-term toxicity. This chemotherapy backbone continues to be used in ongoing Children's Oncology Group studies.)

(This paper provides one example of utilizing FDG-PET response to therapy as part of risk stratification for treatment decisions. These investigators found that early (after two cycles of chemotherapy) PET response was associated with improved event free and overall survival.)

(This article reviews the recent European experience with management of localized LP Hodgkin Lymphoma with surgery alone. Approximately 60% of patients were apparently cured with surgery alone, while those with progressive disease were typically able to be salvaged without significant toxicity.)

(This article reviews the experience of five centers with children and young adults who developed secondary malignancies after treatment for Hodgkin Lymphoma. 11% of survivors experienced a secondary malignancy with an increased risk in girls and those who received higher radiation doses.)

(This paper discusses targeted immunotherapy against CD30 for HL and anaplastic large cell lymphoma using brentuximab vedotin. Included is information on the United States Food and Drug Administration approval of brentuximab vedotin for the treatment of relapsed and refractory HL.)

Ongoing controversies regarding etiology, diagnosis, treatment

Clinical trials to optimally treat pediatric Hodgkin Lymphoma are ongoing through the Children's Oncology Group and other international pediatric oncology cooperative groups. Work continues on improved risk stratification, reduction of radiation exposure, development of new chemotherapy agents and strategies particularly for recurrent or refractory disease, and minimization of long-term effects of therapy.

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